University of Bath PHD The syntheses of morphine glycosides Lacy, Christopher Award date: 1995 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 24. Sep. 2021 THE SYNTHESES OF MORPHINE GLYCOSIDES Submitted by Christopher Lacy for the degree of Ph.D of the University of Bath 1995 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may not be consulted, photocopied or lent to other libraries without the permission of the author for three years from the date of acceptance of the thesis. UMI Number: U601753 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U601753 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 To my Mother and Father ABSTRACT The morphine metabolite morphine-6-glucuronide is a more effective and longer lasting analgesic drug than morphine with fewer side effects. Unfortunately, morphine is also metabolised to morphine-3-glucuronide, a compound which antagonises the analgesic effect of morphine. Since the 3-glucuronide is formed in greater abundance than the6 -glucuronide, there is much interest in using the latter, rather than morphine, as a pain killing drug. Syntheses of morphine- and codeine- 6-glucuronides have been reported by Yoshimura et al. 118, but we have been unable to reproduce the methods described and to obtain the products in a pure form. We have significantly improved the coupling procedure by boiling 3-acetylmorphine and methyl bromo-2,3,4-tri-0-acetylglucopyranosyl uronate in toluene in the presence of silver carbonate on Celite (1:1), giving the adduct which can be deprotected by treatment of sodium hydroxide and purification by elution through a C-18 cartridge to afford pure morphine- 6-glucuronide. Also described are syntheses of the related morphine- 6-glucoside, codeine- 6-glucuronide, and codeine- 6- glucoside using similar methodology. Other targets are CH2 isosteres of morphine- 6-glucuronide which may provide valuable insight into the nature(s) of the opioid receptors. Athough we were unable to complete these syntheses in the time available, some useful investigations were carried out which may provide more focussed direction in future work. ACKNOWLEDGEMENTS The work described in this thesis was carried out in the Organic Chemistry Department of the University of Bath between October 1991 and September 1994. Financial support from Macfarlan-Smith is gratefully acknowledged. I am most grateful to Prof. Malcolm Sainsbury, my supervisor, not only for handing me this project but for his trust, calming influence, and constant source of encouragement and ideas. Special thanks to Prof. Grant Buchanan for providing me with much appreciated help and references in sugar chemistry, and to Dr. Richard Kinsman for his help with the use of C-18 cartridges. I must also thank my industrial supervisors Dr. John Davies and Dr. Mike McPherson for their patience, interest, and helpful discussions. My appreciation goes to the technical staff at the University of Bath for then- invaluable services. Special thanks go to Mr. John Bradley and Mr. Russel Barlow (organic stores), Mr. Dave Wood and Mr. Harry Hartnell (n.m.r. spectroscopy), Mr. Alan Carver (elemental microanalysis), Mr. Chris Cryer (mass spectrometry), Mrs. Jo Curtis, and especially to June and Freda Finally, 1 must respect my good friends Matthew Sage, Alan Graham, Simon Diston, Kevin Williams, and Andrew Gaskell for keeping me wild, Sarah Cosway for keeping me tame, and everyone else 1 worked with, especially Dave Brown, Ali Ninan, Martin Wills, and Matthew Fletcher, for being there when I needed them. Good luck to Maxson Liu with the future work from this project ABBREVIATIONS Ac acetyl AUC area under curve BF3.Et20 boron trifluoride etherate (3 LPT P lipotropin Bn benzyl Bu butyl CNS central nervous system conc. concentrated CPM cyclopropyl methyl CSF cerebrospinal fluid DCE dichloroethane DCM dichloromethane DEAD diethylazodicarboxylate DME dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide ED50 effective dose - dosage effective to 50% population eq equivalents Et ethyl GIT gastrointestinal tract g!y glycine i.c.v. intracerebroventricular 'Pr isopropyl i.r. infrared spectroscopy LDso lethal dose - dosage lethal to 50% population leu leucine M3G morphine-3-glucuronide M6G morphine-6-glucuronide m-CPBA meta-chloroperbenzoic acid Me methyl met methionine MHP mouse hot-plate test m.s. mass spectroscopy n- neo n-pent neo-pentyl n.m.r. nuclear magnetic resonance 0- ortho OPC organotin phosphate condensate phe phenylalanine Pr propyl py pyridine Rf retention factor s.c. subcutaneous TBAF tetrabutylammonium fluoride 'BDMS 'butyldimethylsilyl 'Bu tertiary-butyl Tf trifluoromethanesulfonyl THF tetrahydrofuran t.l.c. thin layer chromatography TMS trimethylsilyl (or tetramethylsilane as n.m.r. standard) t x a 2 thromboxane-A 2 UDP uridine diphosphate UDPGA uridine diphosphate glucuronic acid UGT uridine diphosphate glucuronosyl transferase For spectral data: n.m.r. s singlet d doublet t triplet q quartet pent pentet m multiplet brd broad J coupling constant (Hz) Ar aryl pyrim pyrimidyl i.r. s strong m medium w weak TABLE OF CONTENTS A. INTRODUCTION 1 1. Pain and Analgesia 1 2. Opioids and their Receptors 6 2.1. Agonist-Antagonist Behaviour of Oioids 6 2.2. Endogenous Opioids and Opioid Receptors 7 3. History of Morphine and Analogues 13 4. Modifications and Effects of Morphine 16 4.1. Hydroxyl Groups at C-3 and C -6 16 4.2. Geometric Modifications 17 4.3. Nitrogen Substituents 18 5. Metabolism of Morphine and Analogues 20 6. Conjugation of Glucuronic Acid 23 6.1. Glucuronides of Exogenous Compounds 23 6.2. Types of Glucuronic Acid Conjugation 23 6.3. Effects 25 7. Glucuronides of Morphine 26 7.1. Morphine- 6-Glucuronide (M 6G) 27 7.2. Morphine-3-Glucuronide (M3G) 30 8 . Goals 32 8.1. Current Knowledge on M 6G Synthesis 32 8.2. CH 2 Isostere Targets 34 B. RESULTS AND DISCUSSION 37 1. Morphine-6-Glucuronide Synthesis 37 1.1. Attempted Reproduction of Prior Art 37 1.2. Mitsunobu Reaction 40 1.3. Attempted Coupling Using Acetyl Activation 42 1.4. Other Activation Methods 44 1.5. Coupling Attempts With Benzylated Sugars 45 1.5.1. Alternative Syntheses of Methyl-2,3,4- tri-O-benzylglucopyranosyl uronate 48 1.5.2. Attempted Couplings 57 1.6. Nucleophilic Displacement of Chloride From a-Chlorocodide 59 1.7. Attempted Glucoside Couplings 61 1.8. Attempted Koenigs-Knorr Glucosidation 63 1.9. Attempted Enzymic Coupling 64 1.10. Couplings Using Silver Carbonate On Celite 65 1.10.1. Deprotection of Glucopyranoside Products 67 1.10.2. Glucuronidation Using Silver Carbonate On Celite 68 1.11. Alternative Claims 73 2. CH2 Isostere Targets 75 2.1. Attempted Synthesis of Morphine- 6-pseudoglucuronide 75 2.1.1. Pseudosugar Methodology 75 2.1.2. Synthesis of Epoxide Precursor 77 2.1.3. Investigation of Coupling Methodology 80 3. C-Glucuronide Target 84 C. EXPERIMENTAL 87 D. REFERENCES 164 1 A. INTRODUCTION 1. Pain and Analgesia Analgesia is an altered behavioural response to pain with diminished ability to perceive pain impulses without loss of consciousness. Pain is the body's defence mechanism, informing the individual of tissue damage during or after its occurrence so that he or she can take evasive action and prevent further damage. However, the mechanism of pain is very complex and the degree of pain is not necessarily proportional to the degree of tissue damage. Often pain exists to a far greater extent than is necessary for its purpose and it is therefore desirable to reduce or abolish its effects. This has been the case since ancient times either with medicines or by more natural means such as meditation. Today, the Western World quite typically prefers the use of medicines and a large area of science is devoted towards discovering new analgesic drugs which are more powerful or less toxic (or both) since the problem is still a vast one. Knowledge of the mechanism of pain is essential if one is to consider the mechanisms of analgesic drug actions. Analgesics acting at peripheral sites such as aspirin 1 are known as anti­ inflammatories and this type of analgesia is completely different from the depressant activity in the central nervous system (CNS) effected by narcotic drugs such as morphine 2.